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  • Frontiers Media SA  (3)
  • Gu, Anxin  (3)
  • 2020-2024  (3)
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  • Frontiers Media SA  (3)
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  • 2020-2024  (3)
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  • 1
    Online Resource
    Online Resource
    Image1.jpg
    Frontiers Media SA ; 2023
    In:  Frontiers in Pharmacology Vol. 14 ( 2023-6-29)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 14 ( 2023-6-29)
    Abstract: Background and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of cancer cells to antitumour drugs. Notch pathway activation is controlled by the cleavage of Notch proteins/receptors mediated by A disintegrin and metalloproteinase 17 (ADAM17); therefore, ADAM17 is a reliable intervention target for anti-tumour therapy to overcome the drug resistance of cancer cells. This work aims to develop and elucidate the activation of Compound 2b , a novel-structured small-molecule inhibitor of ADAM17, which was designed and developed and its therapeutic efficacy in NSCLC was assessed via multi-assays. Methods and results: A lead compound for a potential inhibitor of ADAM17 was explored via pharmacophore modelling, molecular docking, and biochemical screening. It was augmented by substituting two important chemical groups [R1 and R2 of the quinoxaline-2,3-diamine (its chemical skeleton)]; subsequently, serial homologs of the lead compound were used to obtain anoptimized compound ( 2b ) with high inhibitory activity compared with leading compound against ADAM17 to inhibit the cleavage of Notch proteins and the accumulation of the Notch intracellular domain in the nuclei of NSCLC cells. The inhibitory activity of compound 2b was demonstrated by quantitative polymerase chain reaction and Western blotting. The specificity of compound 2b on ADAM17 was confirmed via point-mutation. Compound 2b enhanced the activation of antitumor drugs on NSCLC cells, in cell lines and nude mice models, by targeting the ADAM17/Notch pathway. Conclusion: Compound 2b may be a promising strategy for NSCLC treatment.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2023.1189245
    DOI: 10.3389/fphar.2023.1189245.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Table_1.docx
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-8-12)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-8-12)
    Abstract: In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo . T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression levels of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.665970
    DOI: 10.3389/fimmu.2021.665970.s001
    DOI: 10.3389/fimmu.2021.665970.s002
    DOI: 10.3389/fimmu.2021.665970.s003
    DOI: 10.3389/fimmu.2021.665970.s004
    DOI: 10.3389/fimmu.2021.665970.s005
    DOI: 10.3389/fimmu.2021.665970.s006
    DOI: 10.3389/fimmu.2021.665970.s007
    DOI: 10.3389/fimmu.2021.665970.s008
    DOI: 10.3389/fimmu.2021.665970.s009
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Table3.DOCX
    Frontiers Media SA ; 2023
    In:  Frontiers in Pharmacology Vol. 14 ( 2023-1-16)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 14 ( 2023-1-16)
    Abstract: Background: Although the role of tumor microenvironment in lung adenocarcinoma (LUAD) has been explored in a number of studies, the value of TME-related signatures in immunotherapy has not been comprehensively characterized. Materials and Methods: Consensus clustering was conducted to characterize TME-based molecular subtypes using transcription data of LUAD samples. The biological pathways and immune microenvironment were assessed by CIBERSORT, ESTIMATE, and gene set enrichment analysis. A TME-related risk model was established through the algorithms of least absolute shrinkage and selection operator (Lasso) and stepwise Akaike information criterion (stepAIC). Results: Four TME-based molecular subtypes including C1, C2, C3, and C4 were identified, and they showed distinct overall survival, genomic characteristics, DNA methylation pattern, immune microenvironment, and biological pathways. C1 had the worst prognosis and high tumor proliferation rate. C3 and C4 had higher enrichment of anti-tumor signatures compared to C1 and C2. C4 had evidently low enrichment of epithelial–mesenchymal transition (EMT) signature and tumor proliferation rate. C3 was predicted to be more sensitive to immunotherapy compared with other subtypes. C1 is more sensitive to chemotherapy drugs, including Docetaxel, Vinorelbine and Cisplatin, while C3 is more sensitive to Paclitaxel. A five-gene risk model was constructed, which showed a favorable performance in three independent datasets. Low-risk group showed a longer overall survival, more infiltrated immune cells, and higher response to immunotherapy than high-risk group. Conclusion: This study comprehensively characterized the molecular features of LUAD patients based on TME-related signatures, demonstrating the potential of TME-based signatures in exploring the mechanisms of LUAD development. The TME-related risk model was of clinical value to predict LUAD prognosis and guide immunotherapy.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2023.1099927
    DOI: 10.3389/fphar.2023.1099927.s001
    DOI: 10.3389/fphar.2023.1099927.s002
    DOI: 10.3389/fphar.2023.1099927.s003
    DOI: 10.3389/fphar.2023.1099927.s004
    DOI: 10.3389/fphar.2023.1099927.s005
    DOI: 10.3389/fphar.2023.1099927.s006
    DOI: 10.3389/fphar.2023.1099927.s007
    DOI: 10.3389/fphar.2023.1099927.s008
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
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